ABSTRACT
What constitutes acceptable toxicity, of course, depends on the potential therapeutic benefit of the drug. There is an implicit assumption with most anticancer
agents that there is a positive correlation between toxicity and efficacy, but most drugs that will be evaluated in phase I trials will prove ineffective at any dose. The problem of defining an acceptably toxic dose is complicated by the fact that patient response is heterogenous: at a given dose, some patients may experience little or no toxicity, while others may have severe or even fatal toxicity. Since the response of the patient will be unknown before the drug is given, acceptable toxicity is typically defined with respect to the frequency of toxicity in the population as a whole. For example, given a toxicity grading scheme ranging from 0 to 5 (none, mild, moderate, severe, life-threatening, fatal), one might define the MTD as the dose where, on average, one out of three patients would be expected to experience a grade 3 or worse toxicity. In that case, grade 3 or worse toxicity in an individual patient would be referred to as “dose limiting toxicity” (DLT). The definition of DLT may vary from one trial to another depending on what toxicities are expected and how manageable they are.
